The present invention relates, in general, to drug delivery and, in particular, to a new and useful device and method for the needle-free delivery of drugs with minimal trauma to tissue and that are suitable for delivering drugs in sensitive areas of the body such as the eye, nasal passageways, mouth and other areas of the body.
Despite the continual advances in medical technology, particularly in the treatment of various diseases such as heart disease, vascular disease, ophthalmic disease, cancer, pain, allergies, orthopedic repair and many other diseases and conditions, there are a significant number of patients for whom conventional surgical and interventional therapies are not feasible or are insufficient to treat the disease or condition. For many patients, medical treatment with drugs and the like is the only feasible treatment available.
There have been many recent advances in drug therapies, particularly with regard to cell or site-specific therapeutics also known as “local” drug delivery. Unlike the systemic administration of therapeutics, typically taken orally or given intravenously, much of the effectiveness of local drug delivery or cell or site-specific therapeutics is based on the ability to accurately and precisely deliver the therapeutics to the targeted site within the body.
Needle injection devices are the most commonly used means for the local delivery or site-specific administration of agents or solutions. Although there have been advances in needle-based drug delivery/injection systems, these systems have significant shortcomings and disadvantages. One such disadvantage is that the use of a needle or other penetrating means to inject the targeted tissue area unavoidably involves making a hole into the target site thereby causing trauma and tissue injury at the local tissue site.
Another disadvantage with this needle penetrating and injection approach is that it is very common for a substantial amount of the injectate to leak back out or exude from the hole created by the needle or penetrating member. Often, this leaked injectate is released systemically throughout the body or is wasted depriving the patient of the prescribed therapy or dosing amounts of the drug. This also results in increased treatment costs and requires more injections, time and agent in order to achieve the desired affect.
Furthermore, it is known that needle injections or penetration into the tissue can traumatize or destroy tissue cells and, as a result, increase a patient's risk of post-operative trauma, pain and discomfort at the local site and surrounding area. This is particularly due to the difficulty in precisely controlling the penetration of the needle during injection. The more injections or penetrations, the greater the cell destruction and tissue trauma that is likely experienced. Still another disadvantage of needle-based injections, especially where multiple injections are required, is the inability to carefully track the location of each injection site so as to prevent the accidental delivery of drug to non-diseased tissue or repeat delivery of the drug to the same injection hole.
Other known drug delivery devices and methods do not involve needle-based drug delivery. Instead, devices such as indwelling catheters are used for releasing the therapeutic agent in a steady, controlled-release fashion. These types of devices could present a greater risk of releasing the agent systemically. Additionally, with these types of devices, it is more difficult to assess the actual dosing of the target area that takes place. Thus, these types of devices have the disadvantages of being less effective, possibly not as safe, and definitely more costly than the commonly known needle injection approaches and technology.
Another condition in which site-specific or local drug delivery is commonly employed is in the treatment of peripheral vascular disease (such as deep vein thrombosis and embolisms). One such treatment is venous lytic therapy, the dissolving of blood clots (thrombus) in the peripheral vasculature (e.g., femoral and iliac arteries and veins). Lytic therapy involves systemically infusing thrombolytics, such as urokinase, streptokinase, reteplase and tPA. Other more recently developed procedures involve directly delivering the thrombolytics into the thrombus site through the use of indwelling infusion catheters. In order to effectively lyse the thrombus, the thrombolytics are typically infused for many hours, even as much as a day or more, increasing the necessary length of hospital stay and the overall cost of the procedure.
One common approach for eliminating a needle in local drug delivery is to use conventional needle-free jet injectors. Needle-free jet injection technology was introduced nearly 40 years ago for use in mass immunization campaigns. Today, more than fifteen companies develop and manufacture jet injectors for the intradermal and transdermal (subcutaneous and intramuscular) delivery of drugs. And while these modern designs offer tremendous improvements in size, cost and convenience over their predecessors, the fundamental functionality has remained unchanged. Principally, compressed gas is used to drive a medicament (either liquid or dry powder) through a single orifice at moderately high speed, allowing the medicament to be deposited in or beneath the skin by piercing through it. One example of a known needle-free jet injector is disclosed in WO 00/35520 and U.S. Pat. No. 6,406,455 B 1 (Willis et al.—assigned to BioValve Technologies, Inc.).
Further, needle-free jet injection has long been touted as a painless procedure, but clinical studies comparing jet injecting devices to a conventional needle and syringe have shown pain scores to be equivalent to that of a 25 ga. needle. In great part, this is due to the size of the injection stream and, thus, the size of the nozzle orifice. Existing devices all use a nozzle orifice of about 0.006″ to 0.008″ in diameter. These conventional needle-free jet injectors are known to incorporate only a single injection chamber and inject the entire drug content through a single plastic nozzle having a typical orifice diameter of 0.006″-0.008″ or 150-200 microns (0.15 mm-0.2 mm). These jet injectors typically deliver volumes ranging from 0.100 cc (100 micro liters) to 0.500 cc (500 micro liters), and even as much as 1 cc (1,000 micro liters). There are several significant limitations with current jet injection technology. First, injection times associated with these conventional needle-free jet injectors are typically several seconds in length, which puts the patient at risk of laceration if they should move (e.g., flinch) or if the injector should be jarred from the injection site during an injection. Second, the perceived pain is equivalent to a conventional needle and syringe. This has perhaps been the greatest single reason why jet injection has not been more widely accepted. Third, jet injectors are prone to deliver so-called “wet injections” where medicine leaks back out through the site of injection, a result that has given rise to concerns about accuracy of the delivered dose.
The first two items, pain and wet injections, are the result of the nozzle orifice size (approximately 0.006″ in current jet injectors). This size resulted more from the practical limitations of plastic injection molding for high volume commercial manufacturing than from any effort at optimizing the size for user comfort and minimization or elimination of any “leaking” of the injected medicament. This trade-off of sub-optimal performance for manufacturability has resulted in a marginalized product that has not enjoyed the market acceptance it otherwise might have.
One particular type of conventional needle free jet is described in U.S. Pat. No. 6,716,190 B1 (Glines et al.) which teaches a device and methods for the delivery and injection of therapeutic and diagnostic agents to a target site within a body. This device and method uses a complex system comprising a nozzle assembly having an ampule body and channels milled or machined within the distal surface of the ampule body. These channels operate as a manifold and are arranged orthogonal to a reservoir orifice. The reservoir orifice ejects or expels the contents contained within the ampule body to the orthogonally arranged channels which channel the contents to a plurality of dispersion orifices orthogonally arranged to the channels. The dispersion orifices are orthogonal to the channels and located within the generally planar distal target-facing surface. Not only is this particular arrangement complex, but it requires high delivery pressures for the contents in the ampule in a range from about 1800 to 5000 psi, with some applications in a range from about 1800 to 2300 psi. Additionally, the dispersion orifices have a diameter of from about 0.1 mm to about 0.3 mm (100 to 300 microns). Even though such a device does not use a needle, the negative outcome involved with using such a device and arrangement is that it is likely to cause excessive trauma to the tissue at the delivery site as well as cause unwanted and unnecessary pain and/or discomfort to the end user or patient due to the required high delivery pressures as well as the relatively large size of the dispersion orifices. Accordingly, the Glines et al. device and method are not suitable for microjet delivery of drugs especially in sensitive areas of the body such as the eye, nasal passageways and mouth or other sensitive areas of the body especially those areas that are easily prone to trauma, pain and discomfort.
Accordingly, there are a number of sensitive areas in the body and disease states that are extremely difficult to treat using local drug delivery. For example, there are a myriad of ophthalmic diseases that are difficult to treat and delivery of the drug to the site of disease, i.e. the eye, is often painful or psychologically uncomfortable for the patient. Relevant examples of these diseases that are extremely difficult to treat include age-related macular degeneration (AMD), diabetic retinopathy, choroidal neovascularization (CNV), macular edema, uveitis, and the like.
For these types of disease, systemic administration of drug commonly yields subtherapeutic drug concentrations in the eye and may have significant adverse effects. Consequently, current treatment for diseases of the eye often involves direct injection of the medicament into the eye via a conventional needle and syringe—a painful and undesirable means of delivery for the patient. Further, chronic treatment requires repeated injections that can result in plaque formations and scarring in the eye, retinal detachment, and endophthalmitis.
As a result of these complications, alternative means of drug delivery to the eye are being developed. Research areas for delivery include iontophoresis, drug-eluding ocular implants, photodynamic therapy, “sticky” eye drops, and the like. And, it is well established that each of these approaches has its own limitations.
For instance, iontophoresis has a practical limit to the size of the drug molecule being delivered. It could not, for instance, be expected to deliver molecules with a molecular weight above 20,000 Daltons. Yet, many new compounds, especially some promising proteins, are well above this size, ranging to as large as 150,000 Daltons.
Additionally, ocular implants require a surgical procedure for implantation and explantation—procedures that are costly, painful, and can result in scarring to the eye. Implants have the further limitation of physical size and the amount of drug that can be loaded or put on board the implant.
It is also known that photodynamic therapy is an unproven technology whose long-term effects are not understood and may well be harmful to the retina. Alternatively, eye drops have long been considered the most convenient (and therefore perceived to be more acceptable) means of delivery of drugs to the eye. Eye drops, however, are very quickly washed out of the eye and afford only minimal delivery of the contained drug.
As a result, “sticky” eye drops, that is eye drops which provide mucosal adhesion, have been developed to prevent the “wash-out” effect. But, the rapidity of the cellular turnover at the surface of the eye is believed to be limiting in the effectiveness of this means of delivery. Further, the mechanism of delivery from eye drops is passive diffusion across the sclera. And, passive diffusion cannot deliver drugs with a molecular weight greater than about 500 Daltons. Still further, the delivery is systemic rather than targeted to the eye itself.
Consequently, there are currently no truly acceptable means of delivering active therapeutic agents to the eye and other sensitive areas of the body, especially the emerging macromolecules that are showing promise in the treatment of a variety of ophthalmic diseases and diseases associated with these other sensitive areas of the body.
To date, there have been no known devices or methods that provide for true needle-free delivery of drugs regardless of size of the drug molecules involved as well as provide for true needle-free delivery of drugs with minimal trauma to tissue and that are suitable for delivering drugs in sensitive areas of the body such as the eye, nasal passageways or mouth.
To date, there have also been no known devices that provide for the true needle-free delivery of drugs wherein the devices are microjet delivery devices that are simple and efficient in design and construction, low cost and easy to manufacture.